Moustafa T. Gabr

Synthesis and aggregation-induced emission properties of pyridine and pyridinium analogues of tetraphenylethylene

Aggregation-induced emission (AIE) is emerging as an important design element in a variety of new fluorescent-based chemical sensors and bio-imaging agents. In particular, derivatives of tetraphenylethylene (TPE) have been widely utilized in this regard as the TPE framework is a reliable AIE-luminogen. To expand the library of AIE active tetraarylethylenes, we have explored the effects of replacing one or two of the phenyl rings in TPE with pyridine. Efficient synthetic routes that deliver mono- and bis-pyridyl tetraarylethylenes have been developed and the luminescent properties of these heterocyclic TPE analogues, along with their corresponding N-methylated pyridinium salts, have been examined.

A turn-on AIE active fluorescent sensor for Hg2+ by combination of 1,1-bis(2-pyridyl)ethylene and thiophene/bithiophene fragments

Fluorescent sensors for Hg2+ that combine aggregation-induced emission (AIE) activity of tetraarylethylenes with metal chelating 1,1-bis(2-pyridylethylene) fragments and thiophene/bithiophene substituents have been prepared and characterized. The sensors exhibit red-shifted and enhanced emission in the presence of Hg2+ in aqueous solution while exhibiting little to no change in fluorescence in the presence of other metal ions. Job plot analyses indicate 2 : 1 sensor : Hg2+ binding stoichiometries in solution. 1H-NMR spectroscopy was also employed to investigate solution phase binding interactions between the sensors and Hg(ClO4)2, and a chelated HgI2–bis(pyridyl) complex has been characterized by X-ray crystallography. The limit of detection for Hg2+ was determined to be 48 nM. In contrast, the fluorescence of structurally analogous materials possessing quinoline rings in place of pyridine groups is completely quenched in the presence of Hg(ClO4)2. The high sensitivity and selectivity displayed by these sensors for Hg2+ over other metal ions may enable monitoring of mercury in aqueous environments.

Platinum(II) Complexes with Sterically Expansive Tetraarylethylene Ligands as Probes for Mismatched DNA

Deficiencies in DNA mismatch repair (MMR) machinery result in greater incidence of DNA base pair mismatches in many types of cancer cells relative to normal cells. Consequently, luminescent probes capable of signaling the presence of mismatched DNA hold promise as potential cancer diagnostic and therapeutic tools. In this study, a series of cyclometalated platinum(II) complexes with sterically expansive tetraarylethylene ligands were synthesized and examined for selective detection of mismatched DNA. Increased steric bulk of the tetraarylethylene ligands in these complexes was observed to correlate with greater preferential luminescence enhancement in the presence of hairpin DNA oligonucleotides containing a mismatched site compared to well-matched oligonucleotides, with the most effective complex displaying ∼14-fold higher emission upon binding CC mismatched oligonucleotides compared to well-matched oligonucleotides. The results indicate binding to mismatched sites in DNA oligonucleotides occurs through metalloinsertion, and the luminescence response increases as a function of thermodynamic destabilization of the mismatch. Luminescence quenching experiments with Cu(phen)22+ and NaI further indicate mismatch binding from the minor groove, consistent with metalloinsertion. Binding to CC mismatched oligonucleotides was also investigated by isothermal titration calorimetry and UV-melting studies. These results demonstrate the efficacy of tetraarylethylene-based platinum(II) complexes for detection of mismatched DNA and establish a new molecular platform for development of organometallic DNA binding agents.

Rhenium Complexes of Bis(benzothiazole)-Based Tetraarylethylenes as Selective Luminescent Probes for Amyloid Fibrils

Probes for monitoring aggregation of amyloid beta (Aβ) peptides are crucial to advance understanding of the molecular pathogenesis of Alzheimers Disease (AD). Here, we report luminescent tricarbonyl rhenium complexes of tetraarylethylene (TAE) ligands featuring bis(benzothiazole) chelating groups in combination with (oligo)thiophene units that have been designed for monitoring amyloid fibrillation. Variation in the number of thiophenes influenced the photophysical properties of these complexes, as well as their binding affinities toward Aβ42 fibrils. All complexes displayed submicromolar Kds for binding Aβ42 aggregates accompanied by up to 34-fold enhanced luminescence and red-shifted emission wavelengths. The high binding affinities and desirable photophysical properties of these complexes render them potential alternatives to established fluorescent Aβ probes such as thioflavin T. Additionally, the general and modular design approach implemented in this study should facilitate development of second-generation TAE-based diagnostic tools for studying protein aggregation in AD and other neurological diseases.

Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors

A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7 nM) and BACE-1 inhibition (IC50 value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.